NF-kB regulates liver cell death during development, regeneration, and neoplastic transformation. For example, we showed that oncogenic Ras- or Raf-mediated transformation of rat liver epithelial cells (RLEs) led to altered NF-kB regulation through IKK complex activation, which rendered these cells more resistant to TGF-b1-induced apoptosis. Thus, based on these findings, we sought to determine whether NF-kB also could be involved in tumor growth of the liver in vivo. Hepatocellular carcinomas (HCCs) derived from bitransgenic mice harboring a double TGF-a/c-myc transgenes targeted specifically to the liver were selected. Compared to HCCs from c-myc single transgenic mice these tumors are characterized by a higher frequency in appearance, lower apoptotic index and a higher rate in cell proliferation. Here we show that NF-kB is activated in HCCs of double TGF-a/c-myc transgenic mice but not in tumors of c-myc single transgenic mice suggesting TGF-a mediates activation of NF-kB. Furthermore, activation of the IKK complex was observed in the HCCs of double TGF-a/c-myc transgenic mice, implicating this pathway in NF-kB induction. Lastly, activation of the Akt/protein kinase B (PKB), which has been recently implicated in NF-kB activation by PDGF, TNF-a and Ras signalling, was also observed. Thus, these studies elucidate an antiapoptotic mechanism by the TGF-a-Akt/PKB-IKKs pathway, which likely contributes to survival and proliferation and thereby accelerating c-myc-induced liver neoplastic development in vivo.